Hereditary hemochromatosis is caused by mutations in the hemochromatosis (HFE) gene and is one of the most common inherited single gene disorders among Caucasians, affecting approximately 1 in 300 individuals. Measurement of serum transferrin-iron saturation has been proposed as a method of population screening for hemochromatosis. Early identification of persons affected by hemochromatosis is important because iron depletion by phlebotomy can prevent the long-term complications of hemochromatosis, which include liver cirrhosis, liver cancer, diabetes mellitus and heart failure. However, at present there is uncertainty regarding the proportion of patients with untreated hemochromatosis who develop such complications. This is a crucial consideration of any proposed plan for screening or treatment of hemochromatosis. Our primary aims are: a. To determine if there is a threshold of serum transferrin-iron saturation level above which there is a significant increase in the risk of developing liver cirrhosis, liver cancer, diabetes mellitus, or heart failure, b. To determine how the risk of developing liver cirrhosis, liver cancer, diabetes mellitus, or heart failure changes with increasing level of serum transferrin-iron saturation. Our secondary aim is to evaluate whether the threshold of serum transferrin-iron saturation level above which there is a significant increase in the risk of iron overload complications is different for men versus women or for alcohol-users versus non-users. We propose to accomplish these aims by analyzing data collected by the first National Health and Nutrition Examination Survey (NHANES I) and the NHANES Epidemiologic Follow-up Study (NHEFS). These studies comprise a nationally representative cohort of 14,407 persons aged 25-74 years with approximately 20 years of follow-up. Our findings will determine whether persons who would be identified as having a high risk of hereditary hemochromatosis as a result of population screening using serum transferrin-iron saturation, actually have an excess risk of developing complications attributed to iron overload. Furthermore, our findings will be valuable in establishing the best threshold points in serum transferrin-iron saturation levels for the diagnosis of hemochromatosis, or for consideration of subsequent genetic testing or iron depletion therapy. Finally, we will investigate whether such threshold points should be different for men versus women, or for alcohol drinkers versus non-drinkers. [unreadable] [unreadable]